As highlighted in the 'Bad Bugs, No Drugs' campaign by the Infectious Diseases Society of America (IDSA), There simply aren't enough new drugs in the pharmaceutical pipeline to keep pace with drug resistant bacterial infections, so-called `superbugs'. Numerous hospitals worldwide have experienced outbreaks of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, one of the six top-priority dangerous ESKAPE microorganisms identified by the IDSA that require the most urgent attention to discover new antibiotics. Sadly, no novel antibiotics against MDR P. aeruginosa will be available for many years to come. Polymyxins (i.e. colistin and polymyxin B) are now being used as the `last-line' of therapy for infections caused by these very problematic MDR pathogens. Most unfortunately, the emergence of polymyxin resistance has been increasingly reported recently. In essence, resistance to polymyxins implies a total lack of antibiotics for treatment of life-threatening infections caused by these Gram-negative bacteria. Research Design: Our research strategy includes R21 and R33 phases. The overall objective of this project is to harness inhaled bacteriophages as natural predators to combat the superbugs in respiratory infections. Our over-arching hypothesis is that inhalation delivery of phages as an aerosol will provide a safe and efficacious local treatment for MDR infections in the lungs. R21 phase includes two Specific Aims: (1) to produce novel phage powder formulations for inhalation aerosol delivery to the lungs, and (2) to establish the validity and utility of these phge formulations by physicochemical characterization and proof-of- concept efficacy study. If the specific milestones in R21 phase are met, the R33 phase will (1) elucidate the mechanism responsible for stabilization of phages in powder formulations, and evaluate the storage stability of the phage inhalation formulations [Specific Aim 3], and in parallel, examine the pharmacokinetics and potential toxicity of inhaled phage formulations [Specific Aim 4]. Finally, in vivo efficacy studies of inhaled phage formulations will be conducted using animal infection models [Specific Aim 5]. Together, these studies will identify the best phage formulation (plus one backup) for further pre-clinical pharmacological evaluations. As phages are already used clinically, there is great potential to rapidly translate our research findings to the clinic. Significance: This project holds great promise for the development of a novel phage therapy for respiratory infections caused by MDR P. aeruginosa. Our inter-disciplinary approach will provide the fastest track and cost effective clinical solutions for inhaled phage therapy to combat the very problematic Gram-negative `superbug'. Overall, this project targets an urgent global unmet medical need and it aligns perfectly with the 2014 NIAID Antimicrobial Resistance Research Strategic Approaches.